title: TAp73 enhances the pentose phosphate pathway and supports cell proliferation.
abstract: TAp73 is a structural homologue of the pre-eminent tumour suppressor p53. However, unlike p53, TAp73 is rarely mutated, and instead is frequently overexpressed in human tumours. It remains unclear whether TAp73 affords an advantage to tumour cells and if so, what the underlying mechanism is. Here we show that TAp73 supports the proliferation of human and mouse tumour cells. TAp73 activates the expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). By stimulating G6PD, TAp73 increases PPP flux and directs glucose to the production of NADPH and ribose, for the synthesis of macromolecules and detoxification of reactive oxygen species (ROS). The growth defect of TAp73-deficient cells can be rescued by either enforced G6PD expression or the presence of nucleosides plus an ROS scavenger. These findings establish a critical role for TAp73 in regulating metabolism, and connect TAp73 and the PPP to oncogenic cell growth.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Du
authors.forename: Peng
authors.initials: P
authors.lastname: Jiang
authors.forename: Anthony
authors.initials: A
authors.lastname: Mancuso
authors.forename: Aaron
authors.initials: A
authors.lastname: Stonestrom
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brewer
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Minn
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Mian
authors.initials: M
authors.lastname: Wu
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D000975:Antioxidants; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000503:physiopathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D051379:Mice; D009249:NADP / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010427:Pentose Phosphate Pathway; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; C454920:delta Np73, mouse; D009249:NADP; D004247:DNA; D005954:Glucosephosphate Dehydrogenase